This invention relates to certain cyclic amine derivatives that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.
Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema, inflammatory bowel diseases and parasitic infections ((see Bousquet, J. et al. N. Eng. J. Med. 323: 1033-1039 (1990) and Kay, A. B. and Corrigan. C. J. Br. Med. Bull. 48:51-64 (1992)). In asthma, eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators. It is established that chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4 activate eosinophils ((see Baggiolini, M. and Dahinden, C. A. Immunol. Today. 15:127-133 (1994), Rot, A. M. et al. J. Exp. Med. 176, 1489-1495, (1992) and Ponath. P. D. et al. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)). However, unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic for eosinophils ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993) and Jose, P. J. et al. Biochem. Biophy. Res. Commun. 207, 788 (1994)). Specific eosinophil accumulation was observed at the site of administration of eotaxin whether by intradermal or intraperitoneal injection or aerosol inhalation ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993); Jose, P. J. et al. J. Exp. Med. 179, 881-887 (1994); Rothenberg, M. E. et al. J. Exp. Med. 181, 1211 (1995) and Ponath. P. D. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)).
The CCR-3 receptor has been identified as a major chemokine receptor which eosinophils use for their response to eotaxin, RANTES and MCP-3. It is expressed predominantly on the surface of eosinophils and is highly selective for eotaxin. When transfected into a murine pre-xcex2 lymphoma line, the CCR-3 receptor bound eotaxin, RANTES and MCP-3 and conferred chemotactic responses on these cells to these chemokines ((see Ponath. P. D. et al. J. Exp. Med. 183, 2437-2448 (1996)).
Recently, studies have shown that pretreatment of eosinophils with an anti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 ((see Heath H. et al. J. Clin. Invest., Vol. 99, #2, 178-184 (1997)) indicating that CCR-3 antagonists are useful for the treatment of eosinophil-mediated inflammatory diseases. PCT Application WO 98/04554 discloses piperidine analogs that are CCR-3 receptor antagonists.
Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma ((R. P. Schleimer et. al., Am. Rev. Respir. Dis., 141, 559 (1990)). The glucocorticoids are believed to inhibit IL-5, IL-3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in the patients ((see Hanania N. A et al., J. Allergy and Clin. Immunol., Vol. 96, 571-579 (1995) and Saha M. T. et al, Acta Paediatrica, Vol. 86, #2, 138-142 (1997)). It is therefore desirable to have an alternative means of treating eosinophil related diseases without incurring these undesirable side effects.
The present invention provides a means of combating eosinophil induced diseases, such as asthma.
In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula (I): 
wherein:
T and U are both nitrogen; or
one of T and U is xe2x80x94Nxe2x80x94 and the other is carbon; or
one of T and U is xe2x80x94(N+R10)xe2x80x94Xxe2x88x92 and the other is carbon where R10 is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, amidoalkyl, sulfonylaminoalkyl, or aralkyl and Xxe2x88x92 is a pharmaceutically acceptable counterion provided that n is 1;
R1 and R2 are, independently of each other, hydrogen or alkyl;
n is an integer from 0 to 2, provided that when n is 0, either T or U is carbon;
m is an integer from 0 to 3;
Ar and Ar1 are, independently of each other, aryl or heteroaryl;
F is alkylene, alkenylene or a bond, provided that when T and U are nitrogen and F is alkylene, then R4 is not aryl.
Each R is independently hydrogen or alkyl, or R together with either R3 or R4 and the atoms to which they are attached form a carbocycle or a heterocycle;
R3 and R4 are, independently of each other, selected from:
(i) hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, cyano or xe2x80x94(alkylene)xe2x80x94C(O)xe2x80x94Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy, provided that when T and U are both nitrogen or one of T and U is xe2x80x94Nxe2x80x94 and the other is carbon, then both R3 and R4 are not hydrogen; or
(ii) R3 and R4 together with the carbon atom to which they are attached form a carbocycle or a heterocycle;
E is xe2x80x94C(O)N(R5)xe2x80x94, xe2x80x94SO2N(R5)xe2x80x94, xe2x80x94N(R6)C(O)N(R5)xe2x80x94, xe2x80x94N(R6)SO2N(R5)xe2x80x94, xe2x80x94N(R6)C(S)N(R5)xe2x80x94, xe2x80x94N(R6)C(O)xe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94 or xe2x80x94N(R6)SO2xe2x80x94 wherein:
R5 is:
(i) hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, heteroalkyl, or xe2x80x94(alkylene)xe2x80x94C(O)xe2x80x94Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy; or
(ii) R5 together with either R3 or R4 and the atoms to which they are attached forms a heterocycloamino group; and
R6 is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl heteroaralkyl, heterocyclylalkyl, heteroalkyl, or xe2x80x94(alkylene)xe2x80x94C(O)xe2x80x94Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy, provided that when T is nitrogen and E is xe2x80x94C(O)N(R5)xe2x80x94, xe2x80x94SO2N(R5)xe2x80x94, xe2x80x94N(R6)C(O)N(R5)xe2x80x94, xe2x80x94N(R6SO2N(R5)xe2x80x94 or xe2x80x94N(R6)C(S)N(R5)xe2x80x94, then m greater than 0;
Q is xe2x80x94R xe2x80x94Wxe2x80x94R8xe2x80x94 wherein:
R7 is an alkylene chain of between 1-6 carbon atoms inclusive;
R8 is a bond or an alkylene chain of between 1-4 carbon atoms inclusive;
W is a bond or a group selected from xe2x80x94C(O)xe2x80x94, xe2x80x94NR9xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)0-2xe2x80x94, xe2x80x94C(O)N(R9)xe2x80x94, xe2x80x94N(R9)C(O)xe2x80x94, xe2x80x94N(R9)SO2xe2x80x94, xe2x80x94SO2N(R9)xe2x80x94, xe2x80x94N(R9)C(O)N(R9)xe2x80x94, xe2x80x94N(R9)SO2N(R9)xe2x80x94 or xe2x80x94N(R9)C(S)N(R9)xe2x80x94 wherein:
R9 is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or xe2x80x94(alkylene)xe2x80x94C(O)xe2x80x94Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy,
provided that when T is nitrogen and U is carbon then W is not xe2x80x94C(O)N(R9)xe2x80x94, and prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt. The disease states include respiratory diseases such as asthma.
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylenexe2x80x9d means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, 2,4-pentadienylene, and the like.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, e.g., acetyl, benzoyl, thenoyl, and the like.
xe2x80x9cAcyloxyxe2x80x9d means a radical xe2x80x94OC(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl, e.g., acetoxy, benzoyloxy, and the like.
xe2x80x9cAcylaminoxe2x80x9d means a radical xe2x80x94NRC(O)R where R is hydrogen or alkyl and Rxe2x80x2 is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl, e.g., acetylamino, trifluoroacetylamino, benzoylamino, methylacetylamino, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CC13, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e.g., cyclopropyl, cyclohexyl, and the like.
xe2x80x9cCarbocyclexe2x80x9d means a saturated, cyclic group of 3 to 6 ring atoms in which all the ring atoms are carbon, e.g., cyclopentyl, cyclohexyl, and the like.
xe2x80x9cMonosubstituted-aminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, e.g., methylamino, (1-methylethyl)amino, phenylamino, and the like.
xe2x80x9cDisubstituted-aminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methylethyl)amino, methylbenzylamino, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one or more substituents, preferably one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, alkoxy, optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxylamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, xe2x80x94OR [where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl], xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, mono or disubstituted amino], xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, amino, monosubstituted or disubstituted amino) xe2x80x94C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl), xe2x80x94COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), xe2x80x94(alkylene)xe2x80x94COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), methylenedioxy, 1,2-ethylenedioxy, xe2x80x94CONRxe2x80x2Rxe2x80x3 or xe2x80x94(alkylene)CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl and heteroaralkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
xe2x80x9cOptionally substituted phenylxe2x80x9d means a phenyl group which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen or alkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl).
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The aromatic radical is optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionally substituted phenyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxyamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, xe2x80x94OR [where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl], xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, mono or disubstituted amino], xe2x80x94C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl), xe2x80x94COOR (where R is hydrogen, alkyl, or optionally substituted phenyl), xe2x80x94(alkylene)xe2x80x94COOR (where R is hydrogen, alkyl or optionally substituted phenyl), methylenedioxy, 1,2-ethylenedioxy, xe2x80x94CONRxe2x80x2Rxe2x80x3 or xe2x80x94(alkylene)xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl or optionally substituted phenyl). More specifically the term heteroaryl includes, but is not limited to pyridyl, pyrrolyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, indolyl, carbazolyl, azaindolyl, benzofuranyl, benzotriazolyl, benzisoxazolyl, purinyl, quinolinyl, benzopyranyl, and derivatives thereof.
xe2x80x9cHeterocycloaminoxe2x80x9d means a saturated or unsaturated monovalent cyclic group of 5 to 8 ring atoms, wherein at least one ring atom is N and optionally contains a second ring heteroatom selected from the group consisting of N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C. The heterocycloamino ring may be fused to a heteroaryl ring, or it may be optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, monosubstituted amino, disubstituted amino, xe2x80x94COOR (where R is hydrogen or alkyl), xe2x80x94XR (where X is O or S(O)n, n is an integer from 0 to 2, and R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl). Representative examples include but are not limited to pyrrolidino, piperidino, 4-benzoylpiperidino, morpholino, piperazino, 4-(4-benzyloxyphenyl)piperazino, indolino, and the like.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cHeterocyclylxe2x80x9d means a saturated or unsaturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2). The heterocyclo ring may be optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, acylamino, amino, monosubstituted amino, disubstituted amino, xe2x80x94COOR (where R is hydrogen or alkyl), xe2x80x94XR (where X is O or S(O)n, where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, aryl, heteroaryl or heteroaralkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl). Representative examples include, but are not limited to tetrahydropyranyl, piperidino, 1-(4-chlorophenyl)piperidino, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl, cycloalkyl, or cycloalkylalkyl radical as defined above, carrying a substituent containing a heteroatom selected from N, O, S(O)n where n is an integer from 0 to 2. Representative substituents include xe2x80x94NRaRb, xe2x80x94ORa or xe2x80x94S(O)nRc, wherein n is an integer from 0 to 2, Ra is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, pyridyl, or xe2x80x94COR (where Rb is alkyl), It is hydrogen, alkyl, xe2x80x94SO2R (where R is alkyl or hydroxyalkyl), xe2x80x94SQNRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl) and Rc is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, monosubstituted amino, or disubstituted amino. Representative examples include, but are not limited to 2-methoxyethyl, benzyloxymethyl, thiophen-2-ylthiomethyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three or six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.
xe2x80x9cAminoalkylxe2x80x9d means an alkyl radical as defined above, carrying one or two amino groups, e,g., 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 1-(aminomethyl)-2-methylpropyl, and the like. xe2x80x9cAmidoalkylxe2x80x9d means an alkyl radical as defined above, carrying a xe2x80x94NRCORa group where R is hydrogen or alkyl and Ra is alkyl as defined above, e,g., xe2x80x94(CH2)2NHCOCH3, xe2x80x94(CH2)3NHCOCH3, and the like.
xe2x80x9cSulfonylaminoalkylxe2x80x9d means an alkyl radical as defined above, a xe2x80x94NRSO2Ra group, e,g., xe2x80x94(CH2)2NHSO2CH3, xe2x80x94(CH2)3NHSO2CH3, xe2x80x94(CH2)2NHSO2C2H5, and the like.
xe2x80x9cCarboxyalkylxe2x80x9d means an alkyl radical as defined above, carrying a carboxy group, e,g., carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-(carboxymethyl)-2-methylpropyl, and the like.
xe2x80x9cAlkoxycarbonylalkylxe2x80x9d means an alkyl radical as defined above, carrying a xe2x80x94COOR group where R is an alkyl group as defined above, e,g., 2-methoxycarbonylethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d means an alkyl radical as defined above, carrying an alkoxy group, e,g., methoxymethyl, 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 1-(methoxymethyl)-2-methylpropyl, and the like.
xe2x80x9cCyanoalkylxe2x80x9d means an alkyl radical as defmed above, carrying a cyano group, e,g., 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-methylpropyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined above e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
xe2x80x9cAralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heterocyclyl group as defined above e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9chaloalkyloxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, or xe2x80x9cheteroaralkyloxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, haloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl respectively as defined above e.g., methoxy, phenoxy, pyridin-2-yloxy, benzyloxy, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9cheterocyclo group optionally mono- or di-substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group;
xe2x80x9cAmino-protecting groupxe2x80x9d refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC), trifluoroacetyl, and the like.
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed xe2x80x9cisomersxe2x80x9d. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and those that are non-superimposable mirror images of each other are termed xe2x80x9cenantiomersxe2x80x9d. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (xe2x88x92)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a xe2x80x9cracemic mixturexe2x80x9d.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the R3 and R4 substituents in a compound of Formula (I) are different, then the carbon to which they are attached is an asymmetric center and the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable counterionxe2x80x9d means an ion having a charge opposite to that of the substance with which it is associated and that is pharmaceutically acceptable. Representative examples include, but are not limited to, chloride, bromide, iodide, methanesulfonate, p-tolylsulfonate, trifluoroacetate, acetate, and the like.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cLeaving groupxe2x80x9d has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkanesulfonyloxy, arenesulfonyloxy, ester, or amino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxylamino, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, sulfhydryl or amino group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The nomenclature used in this application is generally based on the IUPAC recommendations, e.g.,
a compound of Formula (I) where T and U are nitrogen, n and m are 1, R, R1, R2 and R3 are hydrogen, R4 is 1-methylethyl, E is xe2x80x94C(O)NHxe2x80x94, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is phenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is RS is named, N-{1(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}benzamide.
a compound of Formula (I) where T and U are nitrogen, n and m are 1, R, R1, R2 and R3 are hydrogen, R4 is 1,1-dimethylethyl, E is xe2x80x94NHC(O)NHxe2x80x94, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is phenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is RS is named, 1-{1(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-yl-methyl]-2,2-dimethylpropyl}-3-phenylurea.
a compound of Formula (I) where T and U are nitrogen, n and m are 1, R, R1, R2 and R3 are hydrogen, E is xe2x80x94C(O)NR5xe2x80x94, R4 and R5 together form a 3-pyrrolino ring, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is 4-methylphenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is RS is named, {2-(RS)-[4-(3,4-dichloro-benzyl)piperazin-1-ylmethyl]-1-(4-methylbenzoyl)-3-pyrroline.
a compound of Formula (I) where T is nitrogen, U is carbon, n and m are 1, R, R1, R2 and R3 are hydrogen, R4 is 1-methylethyl, E is xe2x80x94C(O)NHxe2x80x94, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is 4-methylphenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is S is named, N-{1(S)-[4-(3,4-dichlorobenzyl)piperidin-1-yl-methyl]-2-methylpropyl}-4-methylbenzamide.
a compound of Formula (I) where T is xe2x80x94N+R10xe2x80x94, U is carbon, m is 1, R, R1, R2 and R3 are hydrogen, R4 is 1-methylethyl, R10 is ethyl, X is iodide, E is xe2x80x94NHC(O)NHxe2x80x94, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is 3,4,5-trimethoxyphenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is R is named, 4-(3,4-dichlorobenzyl)-1-ethyl-1-{3-methyl-2(R)-[3-(3,4,5-trimethoxyphenyl)ureido]butyl}-piperidinium iodide.
a compound of Formula (I) where T is xe2x80x94N+R10xe2x80x94, U is carbon, m is 1, R, R1, R2 and R3 are hydrogen, R4 is 1-methylethyl, R10 is methyl, X is chloride, E is xe2x80x94C(O)NHxe2x80x94, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is 4-(2-aminoethyl)phenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is R is named, 1-{2-(R)-[4-(2-aminoethyl)benzoylamino]-3-methylbutyl}-4-(3,4-dichlorobenzyl)-1-methyl-piperidinium chloride.
Representative compounds of this invention are as follows:
I. Representative compounds of Formula (I) where T and U=nitrogen; m and n=1; R=R1=R2=R3=hydrogen; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94C(O)NHxe2x80x94 and other groups are as defined below are:
xe2x80x83and are named as:
2. N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2,2-dimethylpropyl}-4-methylbenzamide dihydrochloride salt.
3. N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methoxybenzamide dihydrochloride salt.
4. N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3,4-methylenedioxybenzamide.
7. N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}picolinamide dihydrochloride salt.
8. N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide dihydrochloride salt.
19. N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-2-naphthaleneamide.
25. N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-2-(thiophene-2-yl)acetamide.
35. N-{1(R)-cyclohexyl-2-[4-(3,4-dichlorobenzyl)piperazin-1-yl]ethyl}-4-chloro-benzamide.
37. N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-3-methylbutyl}-4-phenylbenzamide.
44. N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-(4-methylphenyl)acrylamide.
II. Representative compounds of Formula (I) where T=nitrogen; and U=carbon; m and n=1; R=R1=R2=R3=hydrogen; F=bond; E=xe2x80x94C(O)NHxe2x80x94 and other groups are as defined below are:
xe2x80x83and are named as:
57. N-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide hydrochloride salt.
59. N-{1(RS)-[4-(4-Amino-5-chloro-2-methoxyphenylcarbonylaminomethyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide.
III. Representative compounds of Formula (I) where T and U=nitrogen; m and n=1; R=R1=R2=R3=hydrogen; Q=xe2x80x94CH2xe2x80x94 and F=bond; E=xe2x80x94C(O)NR5xe2x80x94; R5 together with R4 and the atoms to which they are attached=heterocycloamino group and other groups are as defined below are:
xe2x80x83and are named as:
77. {1-(4-Methylbenzoyl)-2(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]}piperidine dihydrochloride salt.
IV. Representative compounds of Formula (I) where T and U=nitrogen; m and n=1; R1=R2=R3=hydrogen; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94NHC(O)NHxe2x80x94 and other groups are as defined below are:
xe2x80x83and are named as:
82. 1-{1(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)urea.
84. 1-{2(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-yl]cyclohexyl}-3-(3-methoxyphenyl)urea.
92. 1-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-benzylurea.
V. Representative compounds of Formula (I) where T=nitrogen; and U=carbon; m and n=1; R=R1=R2=R3=hydrogen; F=bond; and E=xe2x80x94NHC(O)NHxe2x80x94 and other groups are as defined below are:
xe2x80x83and are named as:
98. 1-{1(S)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-(3-methoxyphenyl)urea.
VI. Representative compounds of Formula (I) where T and U=nitrogen; m and n=1; R=R1=R2=R3=hydrogen; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94NHC(S)NHxe2x80x94 and other groups are as defined below are:
xe2x80x83and are named as:
107. 1-{1(RS)-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-methylpropyl}-3-(3-methylphenyl)-2-thiourea.
111. 1-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-yl]-3-methylbutyl}-3-(2,4-diflurophenyl)-2-thiourea.
VII. Representative compounds of Formula (I) where T and U=nitrogen; m and n=1; R=R1=R2=R3=hydrogen; F=bond; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94SO2NHxe2x80x94 and other groups are as defined below are:
xe2x80x83and are named as:
117. N-{1(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-flourobenzenesulfonamide.
120. N-{1(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-3-methylbutyl}-2,4-flourobenzenesulfonamide.
VIII. Representative compounds of Formula (I) where T and U=nitrogen; m and n=1; R1=R2=R3=hydrogen; F=bond; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94NHC(O)xe2x80x94 and other groups are as defined below are:
and are named as:
128. 2(RS)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-N-(4-methylphenyl)propionamide dihydrochloride salt.
130. 2(R)-[4-(3,4-Dichlorobenzyl)piperazin-1-ylmethyl]-N-(4-methylphenyl)cyclopentane-1-(R)-carboxamide dihydrochloride salt.
IX. Representative compounds of Formula (I) where T=carbon; U=nitrogen; n=1; R=R1=R2=R3=hydrogen; F=bond; and Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94C(O)NHxe2x80x94 and other groups are as defined below are:
xe2x80x83and are named as:
133. N-{1-[1(RS)-[1-(3,4-Dichlorobenzyl)piperazin-4-ylmethyl]-2-methylpropyl}-4-methylbenzamide.
X. Representative compounds of Formula (I) where T=xe2x80x94N+R10xe2x80x94; U=carbon; m=1; R=R1=R2=R3=hydrogen; F=bond; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94C(O)NHxe2x80x94 and other groups are as defined below are:
XI. Representative compounds of Formula (I) where T=carbon; U=xe2x80x94N+R10xe2x80x94; m=0; R=R1=R2=R3=hydrogen; F=bond; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94C(O)NHxe2x80x94 and other groups are as defined below are:
XII. Representative compounds of Formula (I) where T=xe2x80x94N+R10xe2x80x94; U=carbon; m=1; R=R1=R2=R3=hydrogen; F=bond; Q=xe2x80x94CH2xe2x80x94; E=xe2x80x94NHC(O)NHxe2x80x94 and other groups are as defined below are: